Activation of group I metabotropic glutamate receptors produces a direct excitation and disinhibition of GABAergic projection neurons in the substantia nigra pars reticulata

A pathological increase in excitatory glutamatergic input to substantia nig ra pars reticulata (SNr) from the subthalamic nucleus (STN) is believed to play a key role in the pathophysiology of Parkinson's disease. We present a n analysis of the physiological roles that group I metabotropic glutamate r eceptors (mGluRs) play in regulating SNr functions. Immunocytochemical anal ysis at the light and electron microscopic levels reveal that both mGuR1a a nd mGluR5 are localized postsynaptically in the SNr. Consistent with this, activation of group I mGluRs depolarizes SNr GABAergic neurons. Interesting ly, although both group I mGluRs (mGluR1 and mGluR5) are expressed in these neurons, the effect is mediated solely by mGluR1. Light presynaptic staini ng for mGluR1a and mGluR5 was also observed in some terminals forming symme tric synapses and in small unmyelinated axons. Consistent with this, activa tion of presynaptic mGluR1a and mGluR5 decreases inhibitory transmission in the SNr. The combination of direct excitatory effects and disinhibition in duced by activation of group I mGluRs could lead to a large excitation of S Nr projection neurons. This suggests that group I mGluRs are likely to play an important role in the powerful excitatory control that the STN exerts o n basal ganglia output neurons.